Hydroxamic acid derivatives and medicaments for treatment of urolithiasis and pyelonephrosis comprising such derivatives

ABSTRACT

A novel compound having the general formula: ##STR1## wherein R 1  is a residual group selected from the group consisting of substituted phenyl, carbonoylaminophenyl and heterocyclic groups, and R 2  is hydrogen or methyl group, and its salts of a pharmacologically acceptable base and a novel medicament containing the compound or its salt mentioned above as a principal component; and the compound and the salt thereof having superior effect for the treatment of urolithiasis and the pyelonephrosis by exhibiting a strong urease inhibitory action, a high transfer rate into the urine and a low toxicity.

This is a division of application Ser. No. 769,847, filed Feb. 17, 1977,now U.S. Pat. No. 4,083,996.

This invention relates to novel hydroxamic acid derivative having thegeneral formula: ##STR2## wherein R₁ is a residual group selected fromthe group consisting of a substituted phenyl group represented by aformula: ##STR3## wherein R₃, R₄ and R₅ are selected from the groupconsisting of hydrogen and a lower alkoxy group, provided that at leastone of them is a lower alkoxy group, and two of them may be linked eachother to form an alkylene dioxy group; a carbonylaminophenyl grouprepresented by a formula: ##STR4## wherein R₆ is a lower alkyl group;and a heterocyclic residue selected from the group consisting of furan,thiophene and pyridine, and R₂ is hydrogen or methyl group, providedthat when R₁ is carbonylaminophenyl group, R₂ is hydrogen, and its saltof a pharmacologically acceptable base, as well as medicaments for theurolithiasis and the pyelonephrosis due to the infection of theurease-producing bacterium, which contain said derivative or salt as aprincipal component.

Said derivative represented by the general formula I is synthesized, forexample, according to the following reaction schema: ##STR5## wherein R₁and R₂ represent the same meanings as defined above, and R₇ represents alower alkyl radical. More particularly, the compound (I) is obtained byreacting a lower alkyl ester of 2-(substituted benzamide) acetic acid oran alkyl ester of N-(heterocyclic carbonyl)-glycine represented by thegeneral formula (II) with hydroxylamine (III).

The reaction is generally carried out in a lower alcoholic solvent as areaction medium, for example, methanol, ethanol, propanol, iso-propanoland the like. This reaction is usually carried out in the presence of analkaline reagent which may be exemplified by an alkali hydroxide, suchas sodium hydroxide, potassium hydroxide and the like, and an alkalinebicarbonates such as sodium bicarbonate, potassium bicarbonate and thelike.

When the reaction product is difficult to crystallize and, therefore,difficult to isolate, there may be employed for example a method whichcomprises once forming a chelate of the product with cupric chloride,copper acetate, copper sulfate and the like, followed by decomposingsaid chelate, and isolating the reaction product.

Typical compounds represented by the general formula (I) are exemplifiedin the following Table 1.

                                      Table 1                                     __________________________________________________________________________    Compounds represented by the formula I                                                                 Molecular                                                                             Elementary Analysis                                                   formula Calculated (%)                                                        Melting point                                                                         Found (%)                                    Compound                                                                            R.sub.1         R.sub.2                                                                            (°C.)                                                                        C   H   N                                    __________________________________________________________________________           ##STR6##       H  C.sub.10 H.sub.12 N.sub.2 O.sub.4 161.0-161.5                                         53.57 53.56                                                                       5.39 5.39                                                                         12.50 12.61                          B                                                                                    ##STR7##       H  C.sub.10 H.sub.12 N.sub.2 O.sub.4 132.0-132.5                                         53.57 53.53                                                                       5.39 5.42                                                                         12.50 12.70                           C*                                                                                  ##STR8##       CH.sub.3                                                                         C.sub.11 H.sub.14 N.sub.2 O.sub.4 151.0-152.0                                         55.45 55.42                                                                       5.92  6.00                                                                        11.76 12.00                          D                                                                                    ##STR9##       H  C.sub.10 H.sub.14 N.sub.2 O.sub.4 177.0-177.5                                         53.57 53.45                                                                       5.39 5.37                                                                         12.50 12.61                          E                                                                                    ##STR10##      H  C.sub.11 H.sub.14 N.sub.2 O.sub.4 137.5-138.5                                         55.45 55.43                                                                       5.92 5.97                                                                         11.76 11.67                          F                                                                                    ##STR11##      H  C.sub.12 h.sub.16 N.sub.2 O.sub.4 150.0-151.0                                         57.13 57.23                                                                       6.39 6.48                                                                         11.11 11.21                          G                                                                                    ##STR12##      H  C.sub.13 H.sub.18 N.sub.2 O.sub.4 . 1/3 H.sub.2                               O 126.0-127.0                                                                         57.34 57.59                                                                        6.91 6.61                                                                        110.28  9.80                         H                                                                                    ##STR13##      H  C.sub.10 H.sub.10 N.sub.2 O.sub.5 156.0-157.0                                         50.42 50.27                                                                       4.23 4.33                                                                         11.76 11.69                          I                                                                                    ##STR14##      H  C.sub.11 H.sub.14 N.sub.2 O.sub.5 139.0-139.5                                         51.96 51.84                                                                       5.55 5.61                                                                         11.02 11.13                          J                                                                                    ##STR15##      H  C.sub.12 H.sub.16 N.sub.2 O.sub.6 154.5-155.5                                         50.70 50.67                                                                       5.67 5.70                                                                          9.86  9.99                          K                                                                                    ##STR16##      H  C.sub.12 H.sub.16 N.sub.2 O.sub.6 133.5-134.5                                         50.70 50.37                                                                       5.67 5.92                                                                          9.86  9.46                           L*                                                                                  ##STR17##      CH.sub.3                                                                         C.sub.11 H.sub.14 N.sub.2 O.sub.4 152.0-153.0                                         55.45 55.39                                                                       5.92 6.03                                                                         11.76 11.92                          M                                                                                    ##STR18##      H  C.sub.11 H.sub.13 N.sub.3 O.sub.4 178.0-179.0                                         52.58 52.40                                                                       5.22 5.37                                                                         16.73 16.63                          N                                                                                    ##STR19##      H  C.sub.11 H.sub.13 N.sub.3 O.sub.4 >200**                                              52.58 52.37                                                                       5.22 5.27                                                                         16.73 16.75                          O                                                                                    ##STR20##      H  C.sub.12 H.sub.15 O.sub.4 N.sub.3 158.5-159.5                                         54.33 54.14                                                                       5.70 5.72                                                                         15.84 15.80                          P                                                                                    ##STR21##      H  C.sub.12 H.sub.15 O.sub.4 N.sub.3 >205**                                              54.33 54.07                                                                       5.70 5.74                                                                         15.84 15.88                          Q                                                                                    ##STR22##      H  C.sub.13 H.sub.17 O.sub.4 N.sub.3 158.0-159.0                                         55.90 55.71                                                                       6.14 6.13                                                                         15.05 15.10                          R                                                                                    ##STR23##      H  C.sub.7 H.sub.8 N.sub.2 O.sub.4 150.0-151.0                                           45.65 45.85                                                                       4.38 4.46                                                                         15.21 15.01                          S                                                                                    ##STR24##      H  C.sub.7 H.sub.8 N.sub.2 SO.sub.3 153.0-153.5                                          41.99 41.89                                                                       4.03 4.02                                                                         13.99 14.25                          T                                                                                    ##STR25##      H  C.sub.8 H.sub.9 N.sub.3 O.sub.3 249.0-251.0                                           49.23 49.00                                                                       4.65 4.68                                                                         21.53 21.71                           U*                                                                                  ##STR26##      CH.sub.3                                                                         C.sub.8 H.sub.10 N.sub.2 SO.sub.3 159.0-160.0                                         44.85 44.90                                                                       4.71 4.80                                                                         13.07 13.16                          __________________________________________________________________________     *Racemate or racemic modification                                             **Decomposition point                                                    

The salts of the compound represented by the general formula (I) withpharmacologically acceptable bases can be exemplified by salts ofinorganic bases, for example, the salts of sodium, potassium, magnesium,aluminium and the like, and salts of organic bases, for example, thesalts of piperidine, morpholine, dimethylamine, diethylamine and thelike.

The urolithiasis is one of incurable diseases in a recent urinary area,wherein the urolithiasis is referred to a general term of diseases ofrenal, ureteral, vesical, urethral, prostatic calculus and the like.

The urolithiasis is classified broadly, in accordance with an origin ofthe calculus, into a phosphate, an oxalate and a ureate calculusdiseases and the like. It is often affirmed clinically that they are ina state of a mixed or complex calculus.

The percentage of the phosphate calculus disease in all calculusdiseases is assumed to be 40-60% inclusive of the mixed calculus fromvarious statistic data, on the basis of all patients.

The phosphate calculus is generally formed according to the followingsteps:

Urea in the urine is decomposed into ammonia by a urease-producingbacterium such as Bacillus proteus infected to the urinary tract; theurine is then alkalized by said ammonia, resulting in deposition of thecalculus as an insoluble phosphate.

One of clinical countermeasure for the phosphate calculus disease at thepresent time is to remove the culculus by means of surgical treatment,and the other is to remove the urease-producing bacterium such asBacillus proteus by an antibiotics for the urinary tract system such asAmpicillin and the like. However, there are many cases to be unable torecover by undergoing surgical treatment, because the phosphate calculusdisease often repeats recurrences. The effect of the antibiotics for theurinary tract to the Bacillus proteus and the like is not alsosufficient, and the administration for a long period of time is notpreferable in viewpoint of by-effects. For such reasons, the thirdtreatment has been desired clinically.

As one of the third treatment, there has been also studied a treatmentwhich comprises administering a urease inhibitor, in order to firstlyinhibit the activity of urease per se, and to secondarily prevent thegeneration of ammonia.

It has been reported that many hydroxamic acid compounds generallyexhibit the particular urease inhibitory action. However, the hydroxamicacid compounds can generally not be easily transferred to the urine in aform having a urease inhibitory action, since their metabolism in thebody is rapidly proceeded.

Recently, J. A. Andersen reported that2-(para-chlorobenzamide)-acetohydroxamic acid (it is commonly named"Benurestat") was used for the experimental treatment of phosphatecalculus of a rat, and showed good results due to its urease inhibitoryaction [Refer to Investigative Urology, vol. 12, No. 5, p. 381 (1975)and U.S. Pat. No. 3,728,380]. However, it is true that, as stated morein detail later, there were seen in trace experiments in vitro the factsthat said compound has strong inhibitory actions against the urease,alkalization of the urine and formation of the calculus, and lowtoxicity, but it will be judged that said compound has a poor usefulnessas medicine, because, in the case when the compound is administered to aliving body (measured six hours from the oral administration to a rat),the transfer rate into the urine is as low as 1.0%.

The inventors have investigated to find out a compound having a strongurease inhibitory action, high transfer rate into the urine and lowtoxicity, and successfully developed the expected object by thisinvention.

The object of this invention is thus to provide novel hydroxamic acidderivative having urease inhibitory action.

Another object of this invention is to provide a pharmaceuticalcomposition for the treatment of urolithiasis and pyelonephrosiscontaining the novel hydroxamic acid derivative.

Further object of this invention is to provide a pharmaceuticalcomposition for the treatment of urolithiasis and pyelonephrosis havinglow toxicity and high transfer rate into the urine, resulting in thatsuccessive administration of the pharmaceutical composition is possible.

The compounds represented by the general formula (I) or their salts withpharmacologically acceptable bases according to this invention aresuperior to the above-mentioned known compound,2-(para-chlorobenzamide)-acetohydroxamic acid for the treatment ofurolithiasis, as shown in the following pharmacological experiments.

Pharmacological examination

Compounds for examination

The following examination compounds are elected, among the knowncompound and the compounds according to this invention.

2-(para-chloro-benzamide)-acetohydroxamic acid

(hereinafter referred to the control compound I)

2-(para-methoxy-benzamide)-acetohydroxamic acid

(hereinafter referred to the Compound A)

2-(meta-methoxy-benzamide)-acetohydroxamic acid

(hereinafter referred to the Compound B)

2-(meta-acetylaminobenzamide)-acetohydroxamic acid

(hereinafter referred to the Compound M)

2-(2-furoilamino)-acetohydroxamic acid

(hereinafter referred to the Compound R)

Item for the examination

(I) Determination of the urease inhibitory action and the transfer rateinto the urine

Method for the test

(i) Determination of the urease inhibitory action

Urease was collected and purified from sword beans (Canavalia gladiata)and mol concentrations of the examination compounds for inhibiting 50%of the activity of the urease were measured by the method of Kobashi etal [Refer to Biochim. Biophys. acta 227, 429-441 (1971)].

(ii) Determination of the transfer rate into the urine

Transfer rates into the urine of the examination compounds weredetermined according to the method of Kobashi et al [Refer toBiochemistry (Japan) vol. 44, No. 5, pp. 187-204 (1972) and YakugakuZasshi vol. 12, pp. 1564-1572 (1973)] by using the male rats of SDstrain having the body weight of about 280 g, administering orally each100 mg/Kg of the compounds, and measuring the urease inhibitory actionin the excreted urine within a specified period of time.

(iii) Calculation of the index

The index was calculated from the resulting values of the aboveexaminations (i) and (ii) according to the following equation: ##EQU1##wherein n is chosen appropriately depending on the value of I₅₀.

The value of the index is referred to as a standard of the ureaseinhibitory power of the administered examination compound in the urine.

It is seen that the larger the value of the index is, the moreeffectively the examination compounds transfer into the urine with aform having the urease inhibitory action. Results of the determination

The urease inhibitory action and the transfer into the urine with theactive form were shown in the respective examination compounds. Theresults are shown in the following Table 2:

                  Table 2                                                         ______________________________________                                        Urease inhibitory action and transfer rate into the urine                     Examination           Transfer rate into the                                  group    50% inhibitory                                                                             urine (%)                                               (5 examples                                                                            concentration (M)                                                                          (mean value ± S. E.)                                 for each of urease    Hours                                                   group)   < I.sub.50 > 0-6      6-24    Index*                                 ______________________________________                                        Control                                                                       compound I                                                                             1.0 × 10.sup.-6                                                                      1.00     0.50    1.00                                   Compound A                                                                             1.7 × 10.sup.-6                                                                      12.00    0.83    7.06                                   Compound B                                                                             1.2 × 10.sup.-6                                                                      12.30    1.50    10.30                                  Compound M                                                                             2.0 × 10.sup.-6                                                                      15.0     0.6     7.5                                    Compound R                                                                             1.3 × 10.sup.-6                                                                      15.5     0.68    11.9                                   ______________________________________                                         *The transfer rate into the urine used for the calculation of the index i     a mean value of the transfer rates into the urine of each animal used,        during 6 hours after administration of the examination compound.              Calculation was carried out with n = 6.                                  

As it is clear from the Table 2, all examination compounds have strongurease inhibitory actions. However, the transfer rates into the urine ofthe respective compounds A, B, M and R are all greater than that of thecontrol compound I. From this results, it is judged that the compoundsA, B, M and R are also superior to the control compound in estimation ofthe index (effect index). More particularly, Indices of the compounds A,B, M and R are 4.2, 6.2, 7.5 and 11.9 respectively, while index of thecontrol compound I is 1.0, as shown in Table 2.

(II) Determination of alkalization of the urine and the arrestmentaction to the calculus formation

Method for determination:

Solutions to be examined were prepared by collecting each 18 ml of freshurine from a normal human, and adding the respective examinationcompounds to each of the urine to make their concentration of 10⁻³ M inone group, and of 2×10⁻⁴ in the other group. On the other hand, samesolutions containing no examination compounds were prepared as blanks.

Proteus mirabilis OM-1, a urease-producing bacterium, was inoculated insaid solutions, so that the number of the bacteria may amount to 10⁶cell/ml, and cultured at 37° C. After 0.8 and 24 hours of the culturetime, pH values of the solutions and amounts by weight of the formed anddeposited calculus were measured. The arrestment ratio of calculusformation was calculated from said values.

Results of the measurement:

The following Table 3 shows results of the determination of thearrestment action to the alkalization of the urine by the examinationcompounds.

                  Table 3                                                         ______________________________________                                        Arrestment action to alkalization of the urine                                Examination                                                                   group                                                                         (5 examples                                                                            Concentra-                                                                              pH value (mean value ± S. E.)                           for each tion of the                                                                             Time (hour) from administration                            group)   compound  0         8       24                                       ______________________________________                                        No addition                                                                            --        6.43f±0.01                                                                           8.80±0.00                                                                          9.00±0.00                             Control  10.sup.-3 M                                                                             6.75±0.003                                                                           6.64±0.02                                                                          7.03±0.01                             Compound I                                                                             2×10.sup.-4 M                                                                     6.79±0.01                                                                            7.30±0.00                                                                          8.51±0.01                                      10.sup.-3 M                                                                             6.40±0.00                                                                            5.40±0.003                                                                         5.58±0.05                             Compound A                                                                             2×10.sup.-4 M                                                                     6.45∓0.00                                                                            6.56±0.02                                                                          8.38±0.02                                      10.sup.-3 M                                                                             6.47±0.01                                                                            5.41±0.01                                                                          6.52±0.003                            Compound B                                                                             2×10.sup.-4 M                                                                     6.45±0.01                                                                            6.84±0.02                                                                          8.71±0.01                                      10.sup.-3 M                                                                             6.78±0.02                                                                            6.79±0.01                                                                          7.08±0.03                             Compound M                                                                             2×10.sup.-4 M                                                                     6.79∓0.01                                                                            7.96±0.02                                                                          8.70±0.00                                      10.sup.-3 M                                                                             6.46±0.00                                                                            5.42±0.01                                                                          6.98±0.02                             Compound R                                                                             2×10.sup.-4 M                                                                     6.44±0.01                                                                            6.65±0.02                                                                          8.52±0.01                             ______________________________________                                    

The following Table 4 shows results of measurement of the arrestmentaction to the calculus formation in the urine.

                  Table 4                                                         ______________________________________                                        Arrestment action to the calculus formation in the urine                                               Arrest ratio to                                                               calculus formation (%)*                                                       (mean value±  S. E.)                              Examination groups       Time (hour) from                                     (5 examples for                                                                           Concentration                                                                              administration                                       each group) of the compound                                                                            8         24                                         ______________________________________                                        Control       10.sup.-3 M                                                                              69.7±9.0                                                                             82.5±8.5                                compound I  2×10.sup.-4 M                                                                        77.2±9.1                                                                              30.6±13.9                              Compound A    10.sup.-3 M                                                                              96.2±0.4                                                                             76.6±6.0                                            2×10.sup.-4 M                                                                        99.0±1.0                                                                             32.0±3.4                                Compound B    10.sup.-3 M                                                                              82.0±9.2                                                                             79.1±8.2                                            2×10.sup.-4 M                                                                        87.5±1.6                                                                             26.2±5.7                                Compound M    10.sup.-3 M                                                                              91.5±5.1                                                                             81.4±5.6                                            2×10.sup.-4 M                                                                        80.1±6.7                                                                             38.8±8.0                                Compound R    10.sup.-3 M                                                                              84.1±5.5                                                                             72.3±8.3                                            2×10.sup.-4 M                                                                        85.6±4.7                                                                             28.4±5.1                                ______________________________________                                         ##STR27##                                                                    As it is obvious in the Tables 3 and 4, compounds A, B, M and R arrested      the alkalization of the urine and the calculus formation in the urine due     to Proteus mirabilis OM-1 inoculated to the urine of a normal human. This     action was equal to, or is rather somewhat strong, as compared with that  

Method for examination:

The examination was achieved by orally administering the examinationcompounds into male rats of SD strain weighing about 230 g,respectively.

Results of the measurement:

The results of the measurement of the acute toxicity (LD₅₀) are shown inthe following Table 5.

                  Table 5                                                         ______________________________________                                        Results of the measurement of the acute toxicity (LD.sub.50)                  Examination group                                                             (10 examples for                                                              each group)          LD.sub.50 mg/Kg                                          ______________________________________                                        Control compound 1   > 5,000                                                  Compound A           > 5,000                                                  Compound B           > 5,000                                                  Compound M           > 5,000                                                  Compound R           > 5,000                                                  ______________________________________                                    

As it is obvious from the Table 5, it was affirmed that the acutetoxicities (LD₅₀) of the compounds A, B, M and R are as low as that ofthe control compound.

(IV) Remarks on the observation of the acute toxicity

(1) Remarks on the observation of the general conditions and remarks onthe dissection

Method for examination:

Eight week-old rats of SD strain (body weight: about 230 g for male andabout 160 g for female) were used as the subject animals. Theexamination compounds were forcedly and orally administered in thefollowing dosages, wherein 14 rats (7 male rats and 7 female rats,respectively) were used.

Compounds A and B: 5,000 mg/Kg, 4,000 mg/Kg, 2,000 mg/Kg

Control Compound I: 5,000 mg/Kg, 3,000 mg/Kg, 1,800 mg/Kg,

1,080 mg/Kg, 648 mg/Kg

Results of the observation:

(i) Table 6 shows remarks on the observation of the general conditions.

                  Table 6                                                         ______________________________________                                        Item                                                                          of the Remarks on the observation of the general conditions                   observ-                                                                              Compound                Control                                        ation  A         Compound B    Compound I                                     ______________________________________                                                         Some extent of                                                                              Decrease of                                    Behav- No change decrease of   voluntary notions                              iour   was ob-   voluntary motions                                                                           was observed in                                                 was observed in                                                                             all administra-                                       served in administration                                                                              tion groups of                                        all admin-                                                                              groups of dosage                                                                            male and in the                                                 of 4,000 mg/Kg and                                                                          administration                                        istration of 5,000 mg/Kg.                                                                             groups of the female                                  groups                  of dosage of                                                                  3,000 mg/Kg and                                                               of 5,000 mg/Kg.                                       No change Hair raising was                                                                            arantic change                                 Symptom                                                                              was ob-   observed in the                                                                             accompanying                                          served in administration                                                                              with dishevelled                                      all admin-                                                                              groups of 4,000                                                                             hair was observed                                     istration mg/Kg and of  in all administra-                                    groups    5,000 mg/Kg.  tion groups of male,                                                          and in the admini-                                                            stration groups                                                               of female of dosage                                                           of 3,000 mg/Kg and                                                            of 5,000 mg/Kg.                                       Smoothly                                                               Body   increased Smoothly      10% decrease on                                Weight in all    increased in all                                                                            average was                                           administra-                                                                             administration                                                                              observed in all                                       tion groups                                                                             groups        administration                                        No change               groups                                         Baited was ob-   No change was Decrease in                                    amount served in observed in all                                                                             baited amount was                                     all admin-                                                                              administration                                                                              observed in all                                       istration groups        administration                                 Number groups                  groups                                         of     Male 1/7  Male 2/7      Male 3/7                                       death                                                                         examples                                                                             Female 0/7                                                                              Female 3/7    Female 0/7                                     ______________________________________                                         *in all cases, death examples were observed only in the administration        group of dosage of 5,000 mg/Kg (LD.sub.50 was more than 5,000 mg/Kg in an     case).                                                                   

(ii) Remarks on the dissection

The dissection was performed, for the death examples, at the time ofdeath and, for the survivor example, after killing by discharging theblood when the observation of the general conditions was finished. Theorgans in the thoracic cavity and the abdominal cavity were closelyobserved with a macroscopic manner. The results are shown in thefollowing Table 7.

                  Table 7                                                         ______________________________________                                        Remarks on the dissection                                                     Servivor example     Death examples                                           ______________________________________                                        Com-   No abnormality was                                                                              Erosion was observed                                 pound A                                                                              observed in thoracic                                                                            in ventriculus or                                           cavity and abdominal                                                                            pars cranialis of                                           cavity in all     duodenum                                                    administration groups                                                  Com-   No abnormality was                                                                              Erosion was observed                                 pound B                                                                              observed in thoracic                                                                            in ventriculus or                                           cavity and abdominal                                                                            pors cranialis of                                           cavity in all     duodenum                                                    administration groups                                                         Blacking change and                                                                             Petechiae and ulcer                                         hypertrophy of spleen were                                                                      were observed in                                     Control                                                                              observed in all admini-                                                                         ventriculus and                                      Com-   stration groups of male,                                                                        dropsy in pars                                       pound I                                                                              and in the administration                                                                       cranialis of duodenum.                                      groups of female of                                                           dosage of more than 1030                                                      mg/Kg. These degrees                                                          depended on the dosage.                                                ______________________________________                                    

(2) Remarks on examination of urine

Method for examination:

To 5 male SD strain rats having the body weight of about 280 g in therespective groups, the examination compounds were forcedly and orallyadministered in a ratio of 100 mg/Kg in each time.

Natural urinations were respectively recovered 6 hours and 6-24 hoursfrom the administration. As for control group wherein no examinationcompound is administered, natural urination was similarly recovered.Amount and pH value of the recovered urine were measured. Further,qualitative reaction concerning the respective items of protein,glucose, ketone substances, and occult blood in the urine was carriedout by using Labstix text paper (manufactured and sold by Ames Company).Judgement was ranked as five levels, that is, (-), (±), (+), (++) and(+++).

Results of Examination

Table 8 shows remarks on examination of urine.

                                      Table 8                                     __________________________________________________________________________    Remarks on Examination of urine                                               Examination                                                                   Item                                                                          Exami-                                                                        nation                  Ketone Occult                                         Groups  Protein Glucose substances                                                                           blood                                          (Respective                                                                           hours   hours   hours  hours                                          5 groups)                                                                             0-6 6-24                                                                              6-6 6-24                                                                              0-6                                                                              6-24 0-6                                                                              6-24                                       __________________________________________________________________________    No Examination                                                                compound is                                                                           +   ±                                                                              -   -   -  -   -   -                                          used                                                                          Compound A                                                                            +   ±                                                                              -   -   -  -   -   -                                          Compound B                                                                            +   ±                                                                              -   -   -  -   -   -                                          Control ++  +++ +++ +++ ++ +++ -   -                                          Compound I                                                                    __________________________________________________________________________

As for amount and pH value of the urine, there was not found thedifference between the Compounds A, B and Control Compound I, ascompared with the group wherein no examination compound is administered.

As clear from the data of the Table 8, there was not found thedifference between the Compounds A and B, as compared with the groupwherein no examination compound is administered, with respect to theitems of protein, glucose, ketone substances and occult blood. On thecontrary, the Control Compound I shows a strong positive reaction withrespect to the items of protein, glucose and ketone substances, and itwas observed that toxicity is strong.

From the summarized remarks on the data of the Tables 6, 7 and 8, it isjudged that safety of the Compounds A and B is outstandingly good. Onthe contrary, it was observed that the Control Compound I brings achange in marasmus or debility accompanying with the decrease in thebody weight. Even in the cases of survivors, it is judged that toxicityis strong, from the facts that there was observed a change in black andhypertrophy of the spleen, and the outstanding positive reaction wasshown in the items of protein, glucose and ketone substances accordingto the remarks on the examination of the urine.

In viewpoint of the results of the above pharmacological examinations,the compounds of the general formula (I) typified by the compounds A, B,M and R are judged to have a great value as medicine for the treatmentof the urolithiasis, since these compounds have strong urease inhibitoryaction, arrestment action to the calculus formation based on said ureaseinhibitory action, large transfer rate into the urine such as about10-15 times of that of the control compound I, and high safety. Further,it is clinically said that the pyelonephrosis caused by the infection ofa urease-producing bacterium such as Bacillus proteus takes a seriousturn due to the toxicity of ammonia produced by decomposition of urea inthe urine, but it is also expected that the compounds of the generalformula (I) are used for the treatment of such pyelonephrosis.

The compounds of the general formula (I) can be administered orally orby injection. Administration amount for the treatment of an adultpatient varies from 25 to 3,000 mg a day, and preferably 1,500 mg a day,for example.

The compounds of the general formula (I) are expected to have a superioreffect for the treatment of the urolithiasis in a form of single use andthey are also expected to have much more effect by using them togetherwith other anti-bacilluses such as Ampicillin, sulfamethoxazole,nitrofurantoin, and the like.

The compounds of the general formula (I) can be produced in a type orform of administration by any conventional processes for thepreparation. Accordingly, this invention includes also pharmaceuticalcompositions suitable for a medicament for human body, which contain atleast one of the compounds of the general formula (I). Such compositionsare provided for use with any required pharmaceutical carrier orexcipient by a conventional method.

These compositions are preferably provided in a suitable form forassimilation or absorption in the digestive system. Tablet and capsulefor oral administration are in an administration form of unit amount,and may contain any conventional excepients such as binders e.g. syrup,gum arabic, gelatin, sorbit, tragacant gum and polyvinyl pyrolidone;constituents e.g. milk sugar, corn starch, calcium phosphate, sorbit andglycine; lubricants e.g. magnesium stearate, talc, polyethylene glycoland silica; disintegrater e.g. potato starch; or acceptable wettingagents e.g. sodium lauryl sulphate. The tablet may be coated by a wellknown method in this art. Liquid preparation for oral administration maybe an aqueous or oily suspension, a solution, a syrup, elixir or thelike, or may be a dried products which can be re-dissolved in water orother suitable vehicles prior to use. Such liquid preparation maycontain conventional additives such as suspension agents e.g. sorbitsyrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxy ethylcellulose, carboxy methyl cellulose, aluminium stearate gel, andhydrogenated edible oil; emulsifiers e.g. lecitin, mono-oleyl sorbitaneand gum arabic; non-aqueous vehicles, e.g. almound oil, fractionatedcoconut oil, oily ester, propylene glycol and ethyl alcohol;antiseptics, e.g. methyl p-hydroxy benzoate, propyl p-hydroxy benzoateand sorbic acid.

The compositions for injection are provided in a form of ampoule foramount of unit administration, or in a form of container for a largeamount of administration with antiseptics. These compositions may be ina form of suspension, solution, or emulsion in an aqueous or oilyvehicle, and may contain a treatment agent such as a suspension agent, astabilizer and/or dispersion agent. On the other hand, the activecomponents may be in a powdery form which can be re-dissolved, prior touse, in an appropriate vehicle, such for example, as sterilized waterfree from exothermic substances.

This invention will be illustrated by the following examples concerningprocesses for synthesis of the compounds of the general formula (I) andformulations containing such compounds.

SYNTHESIS EXAMPLE 1 Synthesis of 2-(para-methoxybenzamide)-acetohydroxamic acid

A solution comprising 112 g (2.0 mols) of potassium hydroxide in 500 mlof methanol was added to a solution comprising 69.5 g (1.0 mol) ofhydroxylamine hydrochloride in 500 ml of methanol. Inorganic saltsformed were filtered off. To the filtrate, 142.4 g (0.6 mols) of ethylester of p-methoxy hippuric acid were added. The mixture was sirred forone hour at a room temperature and allowed to stand overnight. Thereaction solution was distilled at 60° C. under reduced pressure toremove the solvent. The residue was dissolved in 500 ml of water. Aceticacid was added to the residue under cooling to make it pH 5.0.Crystalline masses formed were recovered by filtration andrecrystallized from ethanol. There were thus obtained 113.8 g of theobject material which exhibits the melting point of 161.0°-161.5° C. Theyield was 84.6.

Elementary analysis of the product for C₁₀ H₁₂ N₂ O₄ gives:

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Calculated (%)                                                                            53.57      5.39       12.50                                       Found (%)   53.56      5.39       12.61                                       ______________________________________                                    

SYNTHESIS EXAMPLE 2 Synthesis of2-(meta-methoxybenzamide)-acetohydroxamic acid

A solution containing 80 g (2 mols) of sodium hydroxide in 400 ml ofmethanol was added to a solution containing 83.4 g (1.2 mols) ofhydroxylamine hydrochloride in 800 ml of methanol. Inorganic saltsformed were filtered off. To the filtrate, 180 g (0.73 mols) of ethylester of meta-methoxy hippuric acid were added. The mixture was stirredfor one hour at a room temperature and allowed to stand overnight. Thereaction solution was heated to 60° C. and the solvent was distilled offunder reduced pressure. The residue was dissolved in 500 ml of water,and acetic acid was added to said solution under cooling, so that pH ofthe solution may reach to 5.0, then the resulting crystals were removedby filtration.

The crystals were recrystallized from iso-propanol. 121.9 g of theobject were thus obtained, which has the melting point of 132.0°-132.5°C. The yeild was 74.5%.

Elementary analysis for the product for C₁₀ H₁₂ N₂ O₄ gives:

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Calculated (%)                                                                            53.57      5.39       12.50                                       Found (%)   53.53      5.42       12.70                                       ______________________________________                                    

SYNTHESIS EXAMPLE 3 Synthesis of2-(meta-acetylaminobenzamide)-acetohydroxamic acid

A solution containing 52.5 g of potassium hydroxide in 200 ml ofmethanol was added to a solution containing 27.8 g of hydroxylaminehydrochloride in 250 ml of methanol with cooling. Inorganic saltsproduced were filtered off. To the filtrate, 79.3 g of ethylmeta-acetylamino hippurate were added. The mixture was stirred for onehour at a room temperature, and allowed to stand overnight. The reactionsolution was distilled at 60° C. under a reduced pressure to remove thesolvent. The residue was dissolved in 200 ml of water. The solution wasmade to pH 5.0 by adding acetic acid under cooling. The crystals formedare collected by filtration and recrystallized from methanol. The objectmaterial was obtained, which has the melting point in the range from178.0° to 179.0° C.

Amount obtained: 54.6 g Yield: 72.5%

Elementary analysis for the product for C₁₁ H₁₃ N₃ O₄ gives:

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Calculated (%)                                                                            52.58      5.22       16.73                                       Found (%)   52.40      5.37       16.63                                       ______________________________________                                    

SYNTHESIS EXAMPLE 4 Synthesis of2-(para-propionylaminobenzamide)-acetohydroxamic acid

A solution containing 13.1 g of potassium hydroxide in 70 ml of methanolwas to a solution containing 7.0 g of hydroxylamine hydrochloride in 50ml of methanol. Inorganic salts formed were filtered off. To thefiltrate, 12.6 g of ethylester of parapropionylamino hippuric acid wereadded. The mixture was stirred for one hour at a room temperature, andallowed to stand overnight. Large amounts of precipitates produced werecollected by filtration and suspended in 150 ml of water. Acetic acidwas added with vigorous stirring to the suspension, so that pH of thesuspension may amount to 5.0. The crystals formed were collected byfiltration and recrystallized from methanol. The object material wasobtained, which has the melting point (decomposition point) higher than205° C.

Amount obtained: 8.7 g Yield: 72.4%

Elementary analysis for the product for C₁₂ H₁₅ N₄ O₃ gives:

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Calculated (%)                                                                            54.33      5.70       15.84                                       Found (%)   54.07      5.74       15.00                                       ______________________________________                                    

SYNTHESIS EXAMPLE 5 Synthesis of 2-(2-furoilamino)-acetohydoxamic acid

A solution containing 16.4 g of potassium hydroxide in 60 ml of methanolwas added to a solution containing 9.7 g of hydroxylamine hydrochloridein 60 ml of methanol with cooling. Inorganic salts produced werefiltered off. To the filtrate, 19.7 g of ethyl N-(2-furuoil)-glycinatewere added. The mixture was stirred for one hour at a room temperature,and allowed to stand overnight. The reaction solution was distilled at60° C. under a reduced pressure to remove the solvent. The residue wasdissolved in 100 ml of water. The solution was made to pH 5.0 by addingacetic acid under cooling. 8.5 g of cupric chloride di-hydrate wereadded thereto, whereby a complex of copper salt was obtained. Thiscomplex was suspended in 100 ml of methanol, and gaseous hydrogensulfide was passed through therein. The precipitate of copper sulfidewas filterred off. The filtrate was distilled at 60° C. under a reducedpressure to remove the solvent. The product was recrystallized frommethanol. The object material was obtained, which has the melting pointin the range from 150.0° to 151.0° C.

Amount obtained: 13.3 g Yield: 72.3%

Elementary analysis of the product for C₇ H₈ N₂ O₄ gives:

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Calculated (%)                                                                            45.65      4.38       15.21                                       Found (%)   45.85      4.46       15.01                                       ______________________________________                                    

SYNTHESIS EXAMPLE 6 Synthesis of 2-(2-thenoilamino)-acetohydroxamic acid

A solution containing 16.4 g of potassium hydroxide in 60 ml of methanolwas added to a solution containing 9.7 g of hydroxylamine hydrochloridein 60 ml of methanol with cooling. Inorganic salt produced was filteredoff. To the filtrate, 21.3 g of ethyl N-(2-thenoil)-glycinate wereadded. The mixture was stirred for one hour at a room temperature, andallowed to stand overnight. The reaction solution was distilled at 60°C. under a reduced pressure to remove the solvent. The residue wasdissolved in 100 ml of water. The solution was made to pH 5.0 by addingacetic acid under cooling. The crystals formed were collected byfiltration and recrystallized from ethanol. The object material wasobtained, which has the melting point in the range from 153.0° to 153.5°C.

Amount obtained: 13.7 g Yield: 68.3%

Elementary analysis of the product for G₇ H₈ N₂ SO₃ gives:

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Calculated (%)                                                                            41.99      4.03       13.99                                       Found (%)   41.89      4.02       14.25                                       ______________________________________                                    

    ______________________________________                                        Preparation example 1: Tablet                                                 ______________________________________                                        2-(para-methoxybenzamide)-                                                    acetohydroxamic acid   10,000 mg                                              mannit                 4,000 mg                                               potato starch          1,000 mg                                               magnesium stearate     100 mg                                                 ______________________________________                                    

According to the above formulation, 160 tablets were prepared byconventional process. Each one of these tablets contained 100 mg of2-(para-methoxybenzamide)-acetohydroxamic acid.

    ______________________________________                                        Preparation example 2: Medicament for injection                               ______________________________________                                        2-(para-methoxybenzamide)-                                                    acetohydroxamic acid 4.0 g                                                    HCO-60 (manufactured and                                                      sold by Nikko Chemicals,                                                      in Japan)            3.0 g                                                    D-sorbit             30.0 g                                                   Potassium hydroxide,                                                          extra pure grade     appropriate amount                                       Distilled water for injection                                                 sufficient to make up the total to                                                                 500 ml                                                   ______________________________________                                    

According to the above formulation, 100 ampoules of the medicament forinjection (5 ml per ampoule) were prepared by conventional manner. Theseampoules were subjected, if required, to isotonic process or hypertonicprocess and sterilization under high pressure. This medicament contains40 mg of 2-(para-methoxybenzamide)-acetohydroxamic acid per ampoule.

    ______________________________________                                        Preparation example 3: Tablet                                                 ______________________________________                                        2-(meta-acetylaminobenzamide)-                                                acetohydroxamic acid    10,000 mg                                             Mannit                  4,000 mg                                              Potato starch           1,000 mg                                              Magnesium stearate      100 mg                                                ______________________________________                                    

According to the above formulation, 100 tablets were prepared by aconventional process. Each one of these tablets contains 100 mg of2-(meta-acetylaminobenzamide)-acetohydroxamic acid.

    ______________________________________                                        Preparation example 4: Capsule                                                ______________________________________                                        2-(meta-propionylainobenzamide)-                                              acetohydroxamic acid    15,000 mg                                             Corn starch             5,000 mg                                              Talc                    20 mg                                                 ______________________________________                                    

According to the above formulation, 100 capsules were prepared by aconventional process. Each one of these capsules contains 150 mg of2-(meta-propionylaminobenzamide)-acetohydroxamic acid.

    ______________________________________                                        Preparation example 5: Tablet                                                 ______________________________________                                        2-(2-furoilamino)-    15,000 mg                                               acetohydroxamic acid                                                          Milk sugar            3,000 mg                                                Potato starch         2,000 mg                                                Mangnesiumstearate    100 mg                                                  ______________________________________                                    

According to the above formulation, 100 tablets were prepared by aconventional process. Each one of these tablets contained 150 mg of2-(2-furoilamino)-acetohydroxamic acid.

    ______________________________________                                        Preparation example 6: Suspension                                             ______________________________________                                        2-(2-thenoilamino)-                                                           acetohydroxamic acid 1.0 g                                                    Sodium carboxymethyl cellulose                                                                     0.2 g                                                    Strawberry syrup     8.0 ml                                                   Plain syrup          16.0 ml                                                  ______________________________________                                    

According to the above formulation, wholly homogeneous suspension wasprepared by a conventional process.

What is claimed is:
 1. A compound having the general formula: ##STR28##wherein R₁ is a substituted phenyl group represented by a formula:##STR29## wherein R₃, R₄ and R₅ are selected from the group consistingof hydrogen and a lower alkoxy group, provided that at least two of themare lower alkoxy groups, which are linked with each other to form analkylene dioxy group; a carbonylaminophenyl group represented by aformula: ##STR30## wherein R₆ is a lower alkyl group; and a heterocyclicresidue selected from the group consisting of furan, thiophene andpyridine, and R₂ is hydrogen or a methyl group, provided that when R₁ isa carbonoylaminophenyl group, the R₂ is hydrogen, and its salt of apharmacologically acceptable base.
 2. The compound and the saltaccording to claim 1, in which the compound is represented by thegeneral formula: ##STR31## wherein R₆ is a lower alkyl group.
 3. Thecompound and the salt according to claim 1, in which the compound isrepresented by the general formula: ##STR32## wherein R₁ is aheterocyclic residue selected from the group consisting of furan,thiophen and pyridine and R₂ is hydrogen or methyl group.
 4. Amedicament for urolithiasis which comprises an effective amount fortreating urolithiasis of a compound having the general formula:##STR33## wherein R₁ is a substituted phenyl group represented by aformula: ##STR34## wherein R₃, R₄ and R₅ are selected from the groupconsisting of hydrogen and a lower alkoxy group, provided that at leasttwo of them are lower alkoxy groups, which are linked with each other toform an alkylene dioxy group; a carbonylaminophenyl group represented bya formula ##STR35## wherein R₆ is a lower alkyl group; and aheterocyclic residue selected from the group consisting of furan,thiophene and pyridine, and R₂ is hydrogen or a methyl group, providedthat when R₁ is a carbonoylaminophenyl group, the R₂ is hydrogen, andits salt of a pharmacologically acceptable base and a pharmaceuticallyacceptable carrier therefor.
 5. A medicament for pyelonephrosis whichcomprises an effective amount for treating pyelonephrosis of a compoundhaving the general formula: ##STR36## wherein R₁ is a substituted phenylgroup represented by a formula: ##STR37## wherein R₃, R₄ and R₅ areselected from the group consisting of hydrogen and a lower alkoxy group,provided that at least two of them are lower alkoxy groups, which arelinked with each other to form an alkylene dioxy group;acarbonylaminophenyl group represented by a formula: ##STR38## wherein R₆is a lower alkyl group; and a heterocyclic residue selected from thegroup consisting of furan, thiophene and pyridine, and R₂ is hydrogen ora methyl group, provided that when R₁ is a carbonoylaminophenyl group,the R₂ is hydrogen, and its salt of a pharmacologically acceptable baseand a pharmaceutically acceptable carrier therefor.
 6. A method fortreating urolithiasis which comprises administering to a patientsuffering from urolithiasis an effective amount for treating theurolithiasis of a compound according to claim
 1. 7. A method fortreating pyelonephrosis which comprises administering to a patientsuffering from pyelonephrosis an effective amount for treating theurolithiasis of a compound according to claim 1.